How all-type dementia risk factors and modifiable risk interventions may be relevant to the
first-generation aging with HIV infection?

 
  • The burden of dementia risk in aging PLHIV is higher than that in the general population once PLHIV have reached 60 +  premature brain aging found consistently…..in some PLHIV with low comorbidities accelerated brain aging can be detected…… cART early initiation is now standard recommendation. However, there is no definitive evidence that it protects against dementia because no study could have been designed to assess this question. Early treatment is both beneficial against progression to AIDS and the occurrence of non-AIDS events [112]. Importantly, AIDS is a risk factor for HAND, so that a reduction of the prevalence of HAND will have an impact on the rate of potential dementia in PLHIV who will be aging while having been treated early.

  • Discussed below: HIV-related immune compromise, chronic immune activation, immune senescence; ART neurotoxicity

 

HIV-related immune compromise, chronic immune activation, immune senescence

 the evidence for premature cognitive and brain aging is stronger than that for accelerated aging. However, this research is based on cohorts where most PLHIV are aged < 60 years old—well before the dementia age range. Furthermore, when looking at specific conditions (i.e., cerebrovascular diseases and stroke), the weight of evidence favors accelerated brain aging

 

There is strong immune and HIV basic science rationale to the parallels between how aging and chronic-treated HIV infection affects the immune system [36, 37, 113, 114]. In chronic PLHIV, premature aging is probably caused through an integrated pathway of aetiologies converging towards chronic immune activation [115], which is worse as a function of HIV-related immune compromise. Beyond the scope of this review, HIV basic science research shows that the mechanisms driving systemic immune activation in chronic HIV infection are multifactorial (i.e., translocation of microbial products from the gastrointestinal tract, low-level detectable virus, persistent viral reservoirs, and co-infections with other highly common viral pathogens such as the human herpes viruses especially cytomegalovirus) [115]. The chronic state of immune activation leads to an inflammatory response characterized by excessive production and/or accumulation of proinflammatory cytokines (TNFα, IL-1β and IL-6), excessive activation of macrophages and monocytes activation markers (CD14, CD163), increased non-specific inflammation (elevated C-reactive protein (CRP) and cystatin C [116]) that further promotes immune activation. And those inflammatory markers are associated with vascular inflammation and coronary atherosclerosis in PLHIV as well as the general population [117]. As individuals grow older, this vicious cycle probably intensifies because of immune senescence [118].

 

Supporting this rationale are findings relating to the Immune Risk Profile [119] in PLHIV. The Immune Risk Profile distinctly identifies an immunological profile of individuals at increased risk of morbidity and mortality in the general population [119] and not surprisingly this profile has been described in treated HIV+ individuals at significantly younger ages [120] lending credence to the hypothesis of premature and potentially accelerated aging in this population. Importantly, there is evidence that the Immune Risk Profile in resource-limited setting is increased due to higher rates of baseline immune compromise [121], and higher background level of immune activation linked in part to a higher exposure to common human herpes viruses [122]. Finally, with increasing focus on chronic immune dysregulation as a direct contributor to AD [123], and an indirect cause through immune-driven vascular damage [124], there is in addition to non-HIV driven age-comorbidities, a plausible pathophysiological pathway of increased dementia risk even in those PLHIV aging with low comorbidities [125].

ART neurotoxicity

Ethical reasons and the trade-off benefit of being HIV-infected and off therapy have precluded the study of potential ART neurotoxicity in RCTs. Nevertheless, pre-cART studies have demonstrated abnormal neurochemical metabolism in HIV-infected adults on reverse transcriptase inhibitors related to brain mitochondrial toxicity [126] similar to the pathophysiological pathway in the peripheral nervous system leading to peripheral neuropathy. Most of the Nucleoside reverse transcriptase inhibitors (NRTIs) used then are not on the market anymore, but their length of use may have caused some vulnerability to brain damage, nevertheless. One drug that has known adverse neuropsychiatric effects (Efavirenz) [127] has been associated in a least a subset of PLHIV with neurocognitive impairment. Any link to dementia in old age is unknown. In all, it is not impossible that some aging PLHIV may be more vulnerable to dementia in part due to ART neurotoxicity. Recent findings including new types of ART would support this hypothesis [128].

The burden of dementia risk in aging PLHIV is higher than that in the general population

The mildest forms of HAND are the most common in the cART era.. The prevalence of HAND has been recently the focus of some debates [56,105], but even when taking the most conservative estimates, it is undeniable that a non-negligible part of the first generation who are aging with HIV infection has a much higher brain vulnerability burdencompared to the general population entering the dementia age range. Furthermore, age is a risk factor for HAND and HAD and it is estimated that once 50 + PLHIV are considered, HAND prevalence goes up by 10%. …..They seem to still have a relapsing/remitting profile, although with greater intervals between episodes, which translate into long-periods of stability [107]. But when studies have long-term endpoints (> 10 years), or in those aged 60 + , progression is detected and even accelerated brain changes [108, 109, 110]. This is true to a greater extent in those with multiple comorbidities and unsurprising when referenced against what is established in the dementia literature (e.g., The Cardiovascular Risk Factors, Aging and Dementia (CAIDE) risk score, see [19] for an overview). Yet, it seems that even in some PLHIV with low comorbidities accelerated brain aging can be detected [108]. More studies are needed, especially once PLHIV have reached 60 + because the finding of accelerated brain aging is not consistent [28]—it is, however, consistent for premature brain aging [111]. How HAND and the probable increasing contribution of vascular brain injury in aging PLHIV will play out deserve attention because these are yet again combined risk factors for all-types of dementia and well-established promoters of neurodegeneration…..Remaining stable on cART is still the best treatment to avoid HAND and avoid HAND progression once it has been diagnosed. Once on stable treatment, between 70 and 80% of PLHIV remain cognitively stable across years [56]. There is a good chance that some strategies to reduce HAND occurrence and progression will also be protective against dementia development, although empirical evidence is needed. cART early initiation is now standard recommendation. However, there is no definitive evidence that it protects against dementiabecause no study could have been designed to assess this question. Early treatment is both beneficial against progression to AIDS and the occurrence of non-AIDS events [112]. Importantly, AIDS is a risk factor for HAND, so that a reduction of the prevalence of HAND will have an impact on the rate of potential dementia in PLHIV who will be aging while having been treated early.

"it is important to recognize that a life-long treated chronic illness whether it is HIV or for example Type I diabetes [18] carries some added risk for dementia as people age. We should, therefore, advocate for an adapted HIV neurogeriatric response and obtain accurate estimates of dementia as people enter the at-risk dementia ages (60 +). This should not be construed as “fear mongering” but rather as appropriate preparedness. It is now widely recognized that there is a pattern of multi-comorbidities in aging PLHIV, some of which are well-established risk factors for dementia [19]—as we will review…...A modeling study has projected that by 2030, about 85% of elderly PLHIV will have at least one non-AIDS comorbidity [7], many of which are recognized factors for dementia…..Age as the number one risk factor for dementia should be specifically considered in the aging HIV population. Indeed, data are converging to show that there is evidence of premature systemic aging, but limited evidence of accelerated systemic aging [20, 26]. Similarly, the evidence for premature cognitive and brain aging is stronger than that for accelerated aging. However, this research is based on cohorts where most PLHIV are aged < 60 years old—well before the dementia age range. Furthermore, when looking at specific conditions (i.e., cerebrovascular diseases and stroke), the weight of evidence favors accelerated brain aging…..the prevalence of geriatric syndromes such as frailty [30, 31, 32], multimorbidity [12, 33], polypharmacy and disability [34] is higher amongst older PLHIV than the general population, and the syndromes are observed at a younger age than expected [26, 35, 36, 37, 38]. In addition, the decline rate in physical activity is faster among seniors with HIV than without HIV [39]. Biological aging as measured by epigenetic aging shows evidence of both premature and accelerated aging in the HIV population [40] including in children [41,42]. Overall, even if we only consider the premature age signal and greater age-prevalence of age-related conditions, this represents a major risk factor for dementia that is higher than in the general population. Its exact effect size determination demands large longitudinal studies with at least 50% age 60 + …….Cardiovascular health and risk factors  - ART neurotoxicity - HIV-related immune compromise, chronic immune activation, immune senescence - Historical and ongoing HIV brain involvement - Cardiovascular health and risk factors and HIV - Psychiatric, psychological and emotional health, alcohol and substance use"